Progressive nervous system deterioration is the major clinical consequences of human lysosomal storage diseases. The pathogenic basis for cell dysfunction and death due to lysosomal hypertrophy remains unknown. Unfortunately only limited success has been achieved in preventing these diseases and effective therapy is not available. Combined ethical and scientific limitations inherent in patient trials make it imperative that research be performed with in vitro cell culture and animal model systems if progress in this important area of research is to continue. Feline GM1 and GM2 gangliosidoses have been thoroughly characterized and represent valuable models for research on human lysosomal storage diseases. Recent discovery of neuronal abnormalities and advances in enzyme replacement therapy in the feline gangliosdoses provide the basis for research on the pathogenesis and therapy of these diseases. Specific problems to be investigated include: (a) evaluate the morphological and functional consequences of ganglioside storage diseases in subcortical systems of cats, (b) investigate the effects of gangliosidoses on brain organization and development, (c) refine cell culture and in vivo systems for use in testing therapeutic modalities and (d) evaluate promising methods for enzyme replacement therapy. In vitro and in vivo model systems of feline gangliosidoses provide optimal conditions for exploring these crucial questions. It is expected that the proposed research will provide valuable insight on the pathogenesis and therapy of these devistating human diseases.